Testosterone supplementation may help improve exercise capacity and metabolic factors in patients with heart failure, a meta-analysis showed.

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A meta-analysis found that testosterone supplementation improved walking, oxygen consumption, fasting glucose, and insulin in patients with heart failure.

Note that routes of testosterone administration, measurement of exercise capacity, and length of follow-up were not the same in all four of the included trials.

Testosterone supplementation may help improve exercise capacity and metabolic factors in patients with heart failure, a meta-analysis showed.

In pooled results from four small, randomized, placebo-controlled trials, testosterone therapy was associated with 16% to 23% relative improvements in walking distance and peak oxygen consumption, according to Justin Ezekowitz, MBChB, of the University of Alberta in Edmonton, and colleagues.

Also, there were improvements in fasting levels of glucose and insulin and in insulin sensitivity, the researchers reported online in Circulation: Heart Failure.

"Given the unmet clinical needs, testosterone appears to be a promising therapy to improve functional capacity in heart failure patients," they wrote.

They added, however, that "adequately powered randomized controlled trials are required to assess the benefits of testosterone in this high-risk population [including] quality of life, clinical events, and safety."

Low testosterone is common in patients with heart failure and has been associated with reduced exercise capacity and poorer clinical outcomes.

To assess the usefulness of supplementing testosterone in these patients, Ezekowitz and colleagues performed a meta-analysis of four randomized trials that included a total of 198 patients (84% male, mean age 67). Most of the patients (71%) had ischemic heart failure. The average left ventricular ejection fraction was 28%.

Two of the studies used intramuscular injections of testosterone and two used a transdermal patch. Treatment lasted 12 to 52 weeks. None of the trials measured baseline or on-treatment testosterone levels.

By any measure used in the studies, testosterone therapy was associated with improvements in exercise capacity compared with placebo.

The researchers noted that the change in 6-minute walk test met the threshold for a clinically important difference calculated in a cohort of patients with chronic lung disease and exceeded the improvements observed with other heart failure treatments, including ACE inhibitors, beta-blockers, and cardiac resynchronization therapy.

The apparent benefits of testosterone therapy could be related to increased cardiac output, increased muscle mass, anti-inflammatory and immunosuppressive effects, a rise in hemoglobin, and enhanced baroreceptor sensitivity, "which has the potential to improve muscle sympathetic nerve activity with concomitant increased muscle arteriole vasodilation and function," according to the researchers.

Although there were no effects on left ventricular ejection fraction, the percentage of patients who improved at least on New York Heart Association class was greater with testosterone (35% versus 9.8%, P=0.003).

The researchers noted that there were no major safety concerns, but acknowledged the small sample sizes and short lengths of follow-up.

One patient died (in the placebo group), and cardiovascular events occurred at similar rates in the testosterone and placebo groups (7% versus 6%, P=1.0).

None of the individual trials showed a significant change in prostate-specific antigen, but the pooled result showed a slight increase with testosterone therapy (0.10 ng/mL, 95% CI 0.04 to 0.16).

"Despite the concern in regards to the long-term risk of prostate cancer," the authors noted, "currently available data [do] not support a link between testosterone replacement therapy and prostate cancer."

They added that they believe the results are generalizable to women with heart failure because of the consistent results seen in the study that included female patients only, and the proposed mechanisms of action.

Ezekowtiz is funded as a New Investigator by the Canadian Institutes of Health Research and Alberta Innovates-Health Solutions. One of his co-authors is funded as a Senior Health Scholar of Alberta Innovates-Health Solutions.

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